The effects of different antineoplastic agents and of pretreatment by modulators on three melanoma lines.
BACKGROUND
The chemotherapy of melanoma patients must be improved because of the naturally poor response and acquired resistance of this disease.


METHODS
The authors used mouse (B16F10) and human (SK-MEL-28 and SK-MEL-1) melanoma lines for in vitro treatment with melphalan, lomustine, fotemustine, and 4-hydroxyanisole (4-HA) alone, combined and after pretreatment with buthionine sulfoximine (BSO), ethacrynic acid (EA), and azelaic acid (AZA).


RESULTS
Melphalan was the most effective individual drug, followed by lomustine, fotemustine, and 4-HA. The simultaneous administration of two agents was disappointing, although some combinations slightly improved the response compared with the individual treatments. Pretreatment with BSO enhanced the cytotoxicity of melphalan and lomustine 10-fold in B16F10 and 7.5-fold in SK-MEL-28, increasing the toxicity of fotemustine in all 3 lines. EA potentiated lomustine and fotemustine 9-fold and melphalan 5-fold in B16F10 and SK-MEL-28. AZA increased the effectiveness of lomustine and fotemustine in B16F10 and to a lower degree in the two human lines. 4-HA was the poorest drug for sensitization; only B16F10 BSO followed by 4-HA treatment demonstrated increased toxicity, and all other combinations with 4-HA were negative or antagonistic. There was a strong relationship between dopa oxidase activity and the toxicity of 4-HA.


CONCLUSIONS
B16F10 was the most sensitive to all treatments and SK-MEL-1 the most resistant. Melphalan was the most active individual drug and 4-HA the least. Combinations of two drugs did not result in improved activity compared with drugs administered alone. Pretreatment with modulator seems to be a potential method for enhancing some treatments.
Rodriguez-Vicente
J
J
Department of Pathology, Faculty of Medicine, University of Murcia, Spain.
Vicente-Ortega
V
V
Canteras-Jordana
M
M
D000818:Animals; D000840:Anisoles / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019328:Buthionine Sulfoximine / Q000008:administration & dosage / Q000494:pharmacology; D003998:Dicarboxylic Acids / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004976:Ethacrynic Acid / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008130:Lomustine / Q000494:pharmacology; D008546:Melanoma, Experimental / Q000201:enzymology / Q000473:pathology*; D008558:Melphalan / Q000494:pharmacology; D051379:Mice; D014442:Monophenol Monooxygenase / Q000378:metabolism; D009607:Nitrosourea Compounds / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000840:Anisoles; D000970:Antineoplastic Agents; D003998:Dicarboxylic Acids; D009607:Nitrosourea Compounds; D009943:Organophosphorus Compounds; D019328:Buthionine Sulfoximine; C009760:mequinol; D008130:Lomustine; D014442:Monophenol Monooxygenase; C010038:azelaic acid; C054368:fotemustine; D004976:Ethacrynic Acid; D008558:Melphalan